HIV-1 is a notorious human pathogen that affects ˜35 million people worldwide. HIV-1 is considered an enveloped virus because its nucelocapsid, which contains the viral genome, is surrounded by a lipid membrane. Membrane fusion of HIV-1 is mediated by the glycoprotein, gp160. gp160 is cleaved by a protease into two noncovalently bonded glycoproteins; gp120 and gp41. gp120, the surface subunit, is essential for recognizing the target cell's surface receptor. gp41, the transmembrane subunit, contains several regions that are responsible for the merge of the viral membrane and the target cell membrane. The fusion peptide, FP, is important for inducing viral entry, promoted by anchoring itself into the host membrane. X-ray crystallography shows that the C- and N-terminal heptad repeats (CHR and NHR) exist as a trimer of hairpins, in one of its final fusion conformations. NHR is able to self-interact forming a central trimeric coiled-coil with three large hydrophobic pockets. The three helical CHR peptides are able to bind NHR in an antiparallel fashion. This formation, referred to as the 6-helix bundle (6HB), is key for successful infection.
α-Helical peptides mimicking NHR and CHR of gp41 are a validated therapeutic approach for membrane fusion. NHR peptides are able to inhibit infection with micromolar concentrations but often aggregate because of their hydrophobic residues. CHR peptides (also referred to as C-peptides) have proven to be more potent and effective than NHR peptides. For example, C34 (residues 628-661 of CHR) is effective at inhibiting HIV-1 viral membrane fusion in nanomolar concentrations. Despite their success, α-helical peptides still have considerable drawbacks, namely cost of production and sensitivity to degradation. Proteolytic stability is a common issue for α-helical peptides because they are often found disordered in solution, which makes them susceptible to degradation thereby limiting their potency in vivo. Thus, there is a need in the art for new strategies to stabilize α-helical peptides.